1. Field of the Invention
The present invention relates generally to the field of treatment of neoplastic disease. More specifically, the present invention relates to novel immunoconjugates and their use in the treatment of neoplastic disease. Even more particularly, the present invention relates to novel immunoconjugates cytotoxic to leukemia cells characterized by expression of the CD33 antigen.
2. Description of the Related Art
Neoplastic disease is one of the leading causes of mortality and morbidity in the Western World. All neoplastic diseases or “cancers” share at least one characteristic, i.e., the involvement of defects in the cellular growth regulatory process. Antigens located on the surface of cancer cells have been useful in distinguishing lymphoid from non-lymphoid leukemias, subtyping of acute myelogenous leukemia, predicting therapeutic outcome and in therapy in vivo or via a bone marrow purging ex vivo. Antigens defining acute non-lymphocytic cells also identify normal hematopoietic cells during early stages of their development.
CD33 provides a useful target antigen for therapy of myelogenous leukemias, as it is expressed in the cell-surface of more than 80% of leukemic isolates from patients with myeloid leukemia with an average density of 10,000 sites/cell. In addition, rapid internalization occurs upon binding of mAb to CD33 both in vitro and in vivo. CD33 antigen is a 67 kilodalton glycoprotein found on normal colony forming unit granulocyte-monocyte (CFU-GM), on a fraction of burst-forming unit-erythroid (BFU-E and CFU-granulocyte, erythroid, monocyte, megakaryocyte) CFU-GEMM, and absent from normal pluripotent stem cells.
Antibodies are proteins normally produced by the immune system of an animal in response to antigenic determinants. Antibodies bind to the specific antigen to which they are directed. The development of specific monoclonal antibodies has provided investigators with a possible means of selectively targeting chemotherapeutic agents to cells which overexpress tumor associated antigens.
Immunotoxins are hybrid molecules consisting of a monoclonal antibody covalently linked or genetically fused to a toxin molecule and are thus able to direct potent cytotoxicity to particular cells. Immunotoxins have several possible advantages over conventional anti-neoplastic agents including selectivity for tumor cells and potential delivery of extremely potent toxins. However, obstacles to effective therapeutic use of immunotoxins for cancer include (a) lack of suitable tumor-specific targets that are not also found on other vital non-tumor cells; (b) loss of toxin potency or mAb activity after conjugation; (c) unwanted cytotoxicity to nontarget cells and tissues resulting from nonspecific internalization of the immunotoxin; (d) immunogenicity of the immunotoxin; and (e) pharmacological inability to target tumor sites adequately.
Currently, no immunotoxin exists that meet the above-mentioned criteria for an effective immunotoxin to treat acute non-lymphoid leukemic cells and acute myelogenous leukemic cells. Thus, there continues to exist a great need and desire in this art for compounds and methods of selectively killing leukemia cells. The present invention fulfills this long-standing need and desire in the art.